This proposal consists of five unrelated projects to prepare structurally novel, biologically active natural products of potential interest as drugs and, in carrying out these syntheses, to develop newsynthetic methods that will be of general interest and utility. (1) Symbioimine, which inhibits osteoclast differentiation and may therefore be of value in the treatment of osteoporosis, will be synthesized using the novel Diels- Alder reaction of a dihydropyridinium salt as the key step. (2) The proline-derived alkaloids jenamidine A, SB-311099, and epohelmins A and B were recently isolated from a variety of sources and have potent biological activity. New chemistry will be developed to synthesize these natural products to confirm the assignments and provide material for further biological evaluation. (3) An unusual bicyclic macrolide, Sch 642305 inhibits bacterial DMAprimase with an EC50 of 70 micromolar making it a lead for the development of new antibacterial agents. A stereochemically simpler macrolide precursor will be prepared and converted to Sch 642305 by a trans-annular Michael reaction as a novel and potentially very efficient route to this type ring system. (4) Abyssomicin C shows antibiotic activity against a variety of Gram-positive bacteria including pathogenic Staphyloccocus aureus strains and drug-resistant strains. A biomimetic synthesis will be carried out using an intramolecular Diels-Alder reaction to form the cyclohexane ring. Epoxidation and ring opening of the epoxide will complete the synthesis. (5) Bisabosqual A inhibits the microsomal squalene syntheses from Saccharomyces cerevisiae, Candida albicans, HepG2 cell and rat liver with IC50 valuesof 0.43, 0.25, 0.95 and 2.5 microgram/mL, respectively, and has broad antifungal activities against various yeasts. The tetracyclic framework and stereochemistry make the synthesis a challenging problem which will be carried out using chemistry developed in our synthesis of the tetracyclic core. (6) A C2-Symmetric hydrazine and the derived C2-symmetric diamine have been prepared in multi-gram quantities from the azine of citronellal their utility in asymmetric synthesis will be explored. These natural product targets are leads for the treatment of osteoporosis and cancer and for the development of new antibiotics. In the course of these studies new methods will be developed that are of general utility for preparing drugs more economically.